荷兰Hubrecht研究所和乌得勒支大学医学中心Geert J. P. L. Kops团队近期取得重要工作进展，他们研究发现核染色体所在的位置决定了分离错误的频率。该项研究成果2022年7月13日在线发表于《自然》杂志上。
在未转化的二倍体细胞系和类器官中，使用易出错的有丝分裂后的单细胞DNA测序，研究人员发现染色体具有不同的分离错误频率，导致非随机的非整倍体景观。从这些细胞中分离和测序单个微核表明，错误分离的染色体也经常优先被包裹在微核中。在两种癌细胞系的天然存在的微核中也发现了类似的偏倚。
研究人员发现，单个染色体的分离错误频率与其在间期核中的位置相关，并表明在纺锤体两极后的外围染色体中是最高的。染色体位置的随机化Cas9介导的实时跟踪和单个染色体的强制重新定位表明，与核中心的距离越大，错误分离的倾向越大。因此，癌症基因组中的染色体碎裂和早期发育中的非整倍体更频繁地发生在较大的染色体上，这些染色体优先位于核外围附近。他们的研究结果揭示了核染色体位置、分离错误频率和微核含量之间的直接联系，这对大家理解肿瘤基因组进化和发育过程中特定非整倍体的起源具有重要意义。
据了解，细胞分裂过程中的染色体分离错误会产生非整倍体和微核，它们会发生大量的染色体重排，如染色体碎裂。然后，选择性压力会形成不同的非整倍性和重排模式（例如在癌症中），但对于特定染色体是否存在分离错误和微核形成的初始偏差尚不清楚。
附：英文原文
Title: Nuclear chromosome locations dictate segregation error frequencies
Author: Klaasen, Sjoerd J., Truong, My Anh, van Jaarsveld, Richard H., Koprivec, Isabella, timac, Valentina, de Vries, Sippe G., Risteski, Patrik, Kodba, Snjeana, Vukui, Kruno, de Luca, Kim L., Marques, Joana F., Gerrits, Elianne M., Bakker, Bjorn, Foijer, Floris, Kind, Jop, Toli, Iva M., Lens, Susanne M. A., Kops, Geert J. P. L.
Issue&Volume: 2022-07-13
Abstract: Chromosome segregation errors during cell divisions generate aneuploidies and micronuclei, which can undergo extensive chromosomal rearrangements such as chromothripsis1,2,3,4,5. Selective pressures then shape distinct aneuploidy and rearrangement patterns—for example, in cancer6,7—but it is unknown whether initial biases in segregation errors and micronucleation exist for particular chromosomes. Using single-cell DNA sequencing8 after an error-prone mitosis in untransformed, diploid cell lines and organoids, we show that chromosomes have different segregation error frequencies that result in non-random aneuploidy landscapes. Isolation and sequencing of single micronuclei from these cells showed that mis-segregating chromosomes frequently also preferentially become entrapped in micronuclei. A similar bias was found in naturally occurring micronuclei of two cancer cell lines. We find that segregation error frequencies of individual chromosomes correlate with their location in the interphase nucleus, and show that this is highest for peripheral chromosomes behind spindle poles. Randomization of chromosome positions, Cas9-mediated live tracking and forced repositioning of individual chromosomes showed that a greater distance from the nuclear centre directly increases the propensity to mis-segregate. Accordingly, chromothripsis in cancer genomes9 and aneuploidies in early development10 occur more frequently for larger chromosomes, which are preferentially located near the nuclear periphery. Our findings reveal a direct link between nuclear chromosome positions, segregation error frequencies and micronucleus content, with implications for our understanding of tumour genome evolution and the origins of specific aneuploidies during development.
DOI: 10.1038/s41586-022-04938-0
Source: https://www.nature.com/articles/s41586-022-04938-0
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
